Engineered AAV vectors cross blood-brain barrier in monkeys
Delivery of genetic cargo to specific cells is one of the big challenges facing the gene therapy field. A particular challenge is delivery to the brain. Now, researchers have developed a family of AAVs that are more than three times better at delivering their cargo to the primate brain than the current leading AAV delivery vehicle, AAV9.
To do it, they used an mRNA-based directed-evolution strategy in multiple strains of mice. In addition, they used a de novo selection in cynomolgus macaques to identify engineered vectors with increased potency in the brain.
The new AAVs can cross the blood-brain barrier, which typically keeps many drugs from getting into the brain. The engineered AAV capsids also accumulate much less in the liver than AAV9, potentially reducing the risk of liver side effects that have been seen in other AAV9-based gene therapies. This family of AAVs, called the PAL family, could be a safer and more efficient way to deliver gene therapies to the brain.
“We generated a massive pool of randomly generated AAV capsids and from there narrowed down to ones able to get into the brain of both mice and macaques, deliver genetic cargo, and actually transcribe it into mRNA,” said Allie Stanton, a graduate student in the lab of Pardis Sabeti, PhD, a professor at Harvard University.
This work is published in Med in the article, “Systemic administration of novel engineered AAV capsids facilitates enhanced transgene expression in the macaque CNS.”
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